title: Identification of Sulfamoylbenzamide derivatives as selective Cathepsin D inhibitors.
abstract: Aspartic proteases play very important role in post translational processing of proteins and several of them are essential for organism's viability. Here we present the enzyme inhibition activities of different Sulfamoylbenzamide derivatives against two aspartic proteases cathepsin D and plasmepsin II. Cathepsin D is an aspartic protease that degrades proteins at acidic pH in the lysosomes, or extracellular matrix. It is overexpressed by epithelial breast cancer cells and hence hyper-secreted. On the other hand plasmepsin II is an essential enzyme of Plasmodium falciperum. Cathepsin D and Plasmepsin II are pivotal drug targets for treatment of breast cancer and malaria respectively. Virtual screening of Sulfamoylbenzamide compounds followed by enzyme inhibition assays revealed these compounds as selective Cathepsin D inhibitors while inactive against Plasmepsin-II. IC50 values of five Sulfamoylbenzamide compounds tested are in range of 1.25-2.0 μM. N-(3-chlorophenyl)-2-sulfamoylbenzamide is identified as the most potent of all tested Sulfamoylbenzamide compounds with IC50 1.25 μM. It was also noted that the docking score of theses compounds was better in case of Cathepsin D as compared to Plasmepsin-II. Docking score ranges from -29.9±1.16 to -35.1±0.13 in case of Cathepsin D, while from -24.0±0.10 to -29.5±0.10 in case of Plasmepsin-II.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, University of Karachi, Karachi, Pakistan.
authors.forename: Waseem
authors.initials: W
authors.lastname: Ahmed
authors.forename: Ishtiaq Ahmad
authors.initials: IA
authors.lastname: Khan
authors.forename: Muhammad Nadeem
authors.initials: MN
authors.lastname: Arshad
authors.forename: Waseeq Ahmad
authors.initials: WA
authors.lastname: Siddiqui
authors.forename: Muhammad Abdul
authors.initials: MA
authors.lastname: Haleem
authors.forename: Muhammad Kamran
authors.initials: MK
authors.lastname: Azim
mesh_terms: D001549:Benzamides / Q000494:pharmacology*; D002402:Cathepsin D / Q000037:antagonists & inhibitors*; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D011480:Protease Inhibitors; D002402:Cathepsin D